DESCRIPTION: The long term goal of this research program is to identify cellular and molecular mechanisms that regulate the formation and plasticity of synaptic connections in CNS tissue. The present proposal will focus on the development of the major postsynaptic specialization in the CNS, the dendritic spine. The principal investigator's previous observations identified three distinct classes of spiny protrusions (filopodia, protospines, and spines) on developing hippocampal dendrites; these protrusions have different dynamic properties (each class progressively more stable), and they emerge sequentially during development. This developmental progression coincides in time with the formation of synapses on dendrites, but the functional relationships between dendritic structure changes, synaptic contact formation, and synaptic activity are poorly understood. The principal investigator will use time-lapse confocal microscopy, electron microscopy, immunocytochemistry, and physiological and molecular perturbations in in vitro rat hippocampal slice and cell cultures to (1) better define the spatiotemporal relationship between synapse formation and dendritic spine development, and (2) determine how cell-cell contacts and synaptic activity may regulate the morphological and molecular development of spines. The principal investigator's primary hypothesis is that nascent synaptic contacts are formed on structurally-dynamic spine precursors, that synaptic activity at these nascent contacts can regulate the developmental plasticity of spine structure, and that this regulation is mediated, in part, by controlling the expression of neural cell adhesion molecules on dendritic surfaces. New information gained from these studies should lead to a fuller understanding of the regulation of synaptic development, and of the relationships between changes in synaptic structure and function. Abnormalities in postsynaptic spine morphology and density have been documented in a variety of developmental disorders and neuropathological conditions such as mental retardation, Alzheimer's Disease, and temporal lobe epilepsy. Moreover, change in synaptic structure and number are thought to underlie normal mental processes, such as learning and memory. Hence, these studies could provide important insight on fundamental mechanisms of synaptic development and plasticity operating over a wide range of normal and abnormal conditions in man.